Many pharmaceutical oral dosage forms for sustained release of drugs are taught in the prior art. Some of these are in form of swellable matrices in which drug release is via tortuous channels controlled by a swelling polymer. Some are reservoir systems in which drug release is via a laser drilled pin hole controlled by osmotic pressure. While some are beads surrounded by a coat impregnated with soluble materials in which drug release is via channels created by the dissolution of the soluble materials. Coats have been used as means to control the site of release of an active ingredient.
U.S. Pat. No. 6,946,146 teaches a coating composition for coating a solid dosage form of a medicament having at least 50% (w/w) by dry weight of a water insoluble polymer insoluble in both acidic, basic and neutral pH, present in the form of an aqueous latex dispersion and a water soluble component present in a weight ratio of about 5 to about 50% (w/w) by dry weight of the coating, the water soluble component being organic and either solid or liquid and said water soluble component being selected from the group consisting of polydextrose, polyalcohol or ester of polyalcohol, a non-polymeric sugar, a non-polymeric sugar alcohol and amino acid, and the ratio of water insoluble polymer to water soluble component ranging from about 95:5 to about 1:1. The solid content in the coating composition ranging from about 5% to about 25%. As discussed below, inherent disadvantages exist in the use of aqueous latex dispersion of water insoluble polymer for coating.
U.S. Pat. No. 6,911,217 teaches a controlled release bead comprising (i) a core unit of a substantially water-soluble or water-swellable inert material; (ii) a first layer on the core unit of a substantially water-insoluble polymer; (iii) a second layer covering the first layer and containing an active ingredient; and (iv) a third layer of polymer on the second layer effective for controlled release of the active ingredient, wherein the first layer is adapted to control water penetration into the core. This approach is complicated by the core requiring protection from water throughout manufacture.
U.S. Pat. No. 6,902,742 describes a multiparticulate modified release composition comprising a first population of active ingredient-containing particles and at least one subsequent population of active ingredient-containing particles, the active ingredient contained in the first population being an opiate and the active ingredient in the subsequent population being an opiate or a non-opiate, wherein the subsequent population of active ingredient-containing particles further comprises a modified release coating or, alternatively or additionally, a modified release matrix material, such that the composition following oral delivery to a subject delivers the active ingredients of the first and subsequent populations in a pulsatile manner. A problem with matrix formulated material is that it is susceptible to dose dumping under feed conditions and a burst effect under fasted conditions.
U.S. Pat. No. 6,251,432 describes a dosage form for delivery of one or more beneficial agents into a fluid, such as liquid enteral nutritional product. The dosage form unit includes a core containing at least one beneficial agent, preferably a marker dye, which is dispersible in the fluid. A latex coating encases the core. The latex coating includes a mixture containing a substantially hydrophobic base material, preferably formed from an emulsion of cellulose acetate microspheres, which is capable of defining a matrix-type membrane, and at least one hydrophilic component being dispersible in the fluid. A dispersible beneficial agent is preferred as one of the hydrophilic components of the latex coating to allow immediate release of the beneficial agent therefrom. Problems with latex coating compositions are discussed below. Furthermore, matrix type membranes are susceptible to dose dumping under feed conditions and a burst effect under fasted conditions.
U.S. Pat. No. 6,022,562 relates to microcapsules for the oral administration of medicinal and/or nutritional active principles, which are smaller than or equal to 1000 micrometers in size and consist of particles which are coated with a coating material consisting of a mixture of a film-forming polymer derivative, a hydrophobic plasticizer, a functional agent and a nitrogen-containing polymer.
U.S. Pat. No. 5,840,335 describes a system for the controlled release of an active agent and is made of a core surrounded by a shell made of a wall formed of a water-insoluble material which is permeable to the passage of an external fluid. The core is comprised of a water soluble active agent and a soluble polymeric adjuvant, such as polyvinyl alcohols, and a cellulose compound such as methyl cellulose, methylethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose and carboxymethyl cellulose, capable of unlimited swelling. Placing swelling materials in the core complicates the manufacturing process.
U.S. Pat. No. 5,783,215 discloses controlled release beads where each bead comprises (i) a core unit of a soluble or insoluble inert material, (ii) a first layer on the core unit comprising an active ingredient dispersed in a hydrophilic polymer, (iii) an optional second layer of hydrophilic polymer covering the first layer, and (iv) an outermost membrane layer effective for controlled release of the active ingredient. The core is not used to contain the drug and therefore lower amounts of the drug are typically loaded in this form.
U.S. Pat. No. 5,759,577 discloses a compressed medicinal tablet comprising a tablet core and a sugar coating, where the sugar contains a dose of a hormonal steroid, a drug and a steroid release rate controlling amount of microcrystalline cellulose, and PVP to aid in application of the sugar coat. The sugar coating technique is time consuming and prone to variability.
U.S. Pat. No. 5,736,159 discloses a controlled release pharmaceutical tablet. This system is based on a core which contains a water soluble osmotic agent, a water-swellable pharmaceutically acceptable polymer and surrounded by a membrane coating made essentially of a modified water insoluble polymer and a water soluble polymer. Inclusion of osmotic agent and swellable polymer complicates manufacturing as the core must be protected from water.
U.S. Pat. No. 5,595,762 describes stabilized pulverulent active agents, compositions made by coating with a coating composition comprising at least one film-forming agent, in proportions of between 2 and 25% by weight of the final mass, and at least one pore-forming agent, in proportions of between 0 and 5% by weight of the final mass.
U.S. Pat. No. 5,458,887 discloses a controlled release dosage form consisting of an osmotic core comprising essentially of a drug and water swellable component selected from the group consisting of hydroxypropylmethyl cellulose and polyethylene oxide wherein the core is surrounded with a coat comprising of a water resistant polymer and a minor amount of a non-toxic water soluble pharmaceutically acceptable compound (e.g., salt crystals) in an amount which is sufficient to dissolve in the gastrointestinal fluid and form a plurality of micropores on the outside of the tablet, the water resistant polymer being microporous to the passage of the gastrointestinal fluid. Drug release is via the passage way created when the water soluble salt crystals is dissolved in contact with the aqueous medium.
U.S. Pat. No. 5,376,388 describes a water soluble drug core surrounded by a hydratable diffusion barrier made of a film-forming polymer such as an acrylic resin or ethyl cellulose and an additive which controls the rate of hydration and permeability of the hydratable diffusion barrier selected from the group consisting of fully esterified acrylic resins containing quaternary amine side chains, lubricant anionic surfactants, plasticizers, inert water soluble materials and mixtures thereof. The present invention does not teach the use of a hydratable diffusion barrier made from esterified acrylic resins and drug release is not controlled by the rate of hydration of the coating.
U.S. Pat. No. 5,126,146 discloses a microporous, cellulosic coating useful in combination with osmotically controlled drug delivery devices. The coating composition consist essentially of a single layer surrounding a core compartment comprising: a latex derived from an aqueous colloidal dispersion of a cellulosic polymer, surfactant, plasticizer and a pore-forming agent selected from the group consisting of urea, dimethyl sulfone, nicotinamide, or an amino acid.
U.S. Pat. No. 4,966,768 describes a sustained release oral dosage form made by compressing an active ingredient plus a high molecular weight hydroxypropylmethylcellulose, methyl cellulose, sodium carboxymethylcellulose and or other cellulose ether. The dosage form in '768 is a matrix system and is subject to dose dumping especially when taken with food.
U.S. Pat. No. 4,963,365 describes a controlled release dosage form which consists essentially of a core containing a medicament; an inner coating layer composed of ethylcellulose and a hydrophobic substance; and an outer coating layer containing a medicament are also disclosed. This dosage form uses only water insoluble substances for its inner coating layer and relies solely on an outer coating layer containing a medicament to obtain the required loading dose for rapid increase in blood concentration of the medicament.
U.S. Pat. Nos. 4,886,668 and 4,880,631 directed to osmotic pumps, for the controlled release of an active substance, teach a core surrounded by a rate controlling water insoluble wall as coat which utilizes a polymer permeable to water but impermeable to solute and a pH insensitive pore forming additive dispersed through the wall.
U.S. Pat. No. 4,765,989 describe an osmotic system comprising a wall comprising, in at least a part, of a semipermeable material that surrounds a compartment. The compartment contains an osmotic composition and drug, and a second and different osmotic composition. The drug is released with aid of osmotic tension via a passageway in the wall that connects the first osmotic composition with the exterior of the system.
U.S. Pat. No. 4,389,393 discloses sustained release therapeutic compressed solid unit dose forms of an active ingredient plus a carrier base comprised of a high molecular weight hydroxypropylmethylcellulose, methyl cellulose, sodium carboxymethylcellulose and or other cellulose ether. This system is subject to dose dumping especially when taken with food.
U.S. Pat. No. 4,330,338 ('338 patent) describes pharmaceutical coatings in the form of aqueous dispersions or latex preparation of a water insoluble polymer, such as ethyl cellulose. Tablet cores coated according to the '338 patent release active agent by diffusion, which can be an exceedingly slow process unless systems with a large surface area are utilized. To expedite release of active agent from tablets coated with, e.g., an ethyl cellulose coating prepared in accordance with the disclosure of the '338 patent, hydroxypropylmethycellulose (HPMC) has been added to the coating. '338 further discloses that HPMC, enhances the water solubility of the ethyl cellulose coats, causing the coating and subsequently the tablet core to rapidly disintegrate in an environment of use such as the intestine. Such rapid disintegration, however, is unsuitable for those applications in which drug is to be delivered continuously over time such as those taught in the present invention.
U.S. Pat. No. 4,31,285 discloses an osmotic device having coat comprising an annealed subcoat and an overcoat, annealed at about 35 degree C. to 65 degree C. for 10 to 72 hours.
U.S. Pat. No. 4,248,856 disclose the use of sugar coating in conjunction with a barrier coating on a core containing medicament and the cellulose polymers hydroxypropyl methylcellulose and ethylcellulose in order to provide controlled release of pharmaceuticals.
U.S. Pat. No. 4,060,598 teaches a coated pharmaceutical tablet comprising a core of active material and at least one layer of a coating made up of a film forming aqueous synthetic resin dispersion (such as polyvinyl esters, polyacrylic acid esters, polyvinyl acetate, polyvinyl chloride or butadienestyrene copolymers) and a water or alkaline soluble material. It further describes the resulting coated tablet as a core surrounded by a continuous porous matrix of synthetic resin formed from the aqueous dispersion which is insoluble in water and insoluble in the gastrointestinal tract. '598 patent also describes the coating as achieving fast disintegrating or enteric disintegrating coating for tablets.
U.S. Pat. No. 4,016,880 describes a tablet having an osmotic material and a sustained release coating. The drug is released through passages in the coating caused by structural weaknesses.
Most of the controlled release technologies described in the prior art above have as a common feature, a rate controlling membrane surrounding a core which comprise of drug and controlled release polymer and/or an osmotic agent or in some cases the core contain no drug. In many of the aforementioned disclosures, the membrane is made from water insoluble polymers, and various additives are added in various forms to alter the permeability of the membrane to allow and control the rate of release of drug. Some of them require the presence of certain ingredients, e.g., osmotic ingredients, for the formulation to function.
The coating and core compositions described in the prior art have disadvantages. Sugar coating of a solid dosage has the drawback of being a very involved process requiring highly skilled operators and it has no application in controlled release drug delivery. The problem with osmotic devices is that they are tedious and difficult to fabricate. Their efficiency and precision is also in doubt as they have been known to break up prematurely or retain some of the drug content during transit in the gastrointestinal tract, which may lead to less drug being released and delivered by such devices. It is, therefore, not uncommon for such devices to contain an overage of drug of at least 10% to account for such inefficiencies in dose delivery. This practice is not economical and presents a danger, especially if potent drugs are used, as these devices have been known to rupture in transit thus releasing excess dose.
There has been a move towards aqueous coating systems such as aqueous based synthetic polymer dispersions which are produced by emulsion polymerization and latex dispersions. This is because these aqueous systems are nonflammable and thus provide no explosion hazard, is substantially free of toxic effects and is innocuous to the environment. However, the use of aqueous systems of polymers for film coating to provide dosage coatings has its draw backs, these systems are subject to bacterial and mold growth without the presence of a preservative agent and the presence of pore forming materials as suggested by the prior art may cause coalescence or coagulation of the latex dispersion, which may render it un-usable. These lattices also require the presence of surfactants in order to stabilize the latex dispersions from coalescence. Furthermore, in order to obtain a coating of uniform thickness and integrity there is need to subject the latex coated dosage form to a curing process by heating under high temperature. Latex dispersions have a high tacking factor, curing tends to result in an irreversible agglomeration of the dosage form and damage of the coating upon separation of the dosage forms. This results in a faster release than with uncured dosage forms.
Use of aqueous coating systems is complicated further by the slow evaporation of water and large amounts of water which must be removed from each coating. Further, many drugs are sensitive to water when exposed to high concentrations for extended periods of time and, accordingly, require initial sealing with water barriers.
The use of additives or soluble components in latex coating compositions as suggested in the prior art can lead to film instability during coating. Films formed with the addition of the soluble component are weaker than the film formed by using the insoluble polymer latex alone. This is because of the mechanisms by which latex films are deposited and formed around a substrate. The film is formed by the coalescence of the polymer latex particles. The presence of the water soluble component which is not soluble or physically compatible with the polymer would prevent complete coalescence of the polymeric particles and thus produces a weaker film. At high concentrations the water soluble component will help cause erosion of the film formed from latex systems. It is therefore critical that the water soluble component is soluble in water and the solubility is in excess of 5% (w/w). Latex systems are limited with regards to the amount of soluble and or swellable components that can be added to the system.
Therefore, there is still a need to develop a stable drug delivery device that can be reproducibly manufactured and have a desired effect of controlled release.